Author's response to reviews Title:Atypical language organization in temporal lobe epilepsy revealed by a passive semantic paradigm Authors: Julia Miro (juliamirollado@gmail.com) Pablo Ripollès (pablo.ripolles.vidal@gmail.com) Diana López-Barroso (dlopezbarroso@gmail.com) Adrià Vilà-Balló (adria.vila.ballo@gmail.com) Montse Juncadella (mjuncadella@bellvitgehospital.cat) Ruth De Diego-Balaguer (ruth.de.diego@gmail.com) Josep Marco-Pallarès (josepmarco@hotmail.com) Antoni Rodríguez-Fornells (arfornells@gmail.com) Mercè Falip (mfalip@bellvitgehospital.cat) Version:3Date:3 March 2014 Author's response to reviews: Dear Dr. Taoufic Alsaadi, Associate Editor of BMC Neurology We wish to thank the Reviewers and editor again for their overall positive comments on our study, as well as for the time dedicated to make useful suggestions that ultimately have improved our manuscript. We have followed your recommendation and the language in the manuscript has been edited by a native-english speaker with scientific expertise. Below you will find the detailed list of paragraphs with language changes included into this revised version of the manuscript. Background (Pages 4-6) - A complication of surgery observed in 30-50% of patients after left ATL resection is a decline in language or verbal memory function [4-7]. - A decrease of regional cerebral metabolism unilateral to the epileptogenic focus has been observed in patients with intractable TLE, usually in temporal and occasionally prefrontal regions [9]. Similarly, the reorganization of language may also affect different productive (located in frontal areas) and perceptive (located in temporal regions) language functions mainly in temporal rather than frontal areas [10, 11]. - Although the tasks employed by epilepsy institutes vary greatly, most fmri paradigms used to determine the language dominance in epileptic populations include language production paradigms such as word or verb generation [11, 13, 15-18], object naming [14], or sentence repetition [11]. - Surprisingly, only a few studies of epilepsy sufferers have used pure passive
tasks such as listening to standard speech [11, 20, 21]. Passive listening paradigms reliably activate the receptive language cortex [22] making it possible to determine hemispheric dominance and identify the areas involved in language processing of TLE patients, which is of the utmost importance in pre-surgical language mapping [10,11]. These tasks commonly bring about activations in Wernicke's area mainly the superior temporal gyrus (STG) and the middle temporal gyrus (MTG), frequently extending into the angular gyrus- but also in the primary auditory area and less often in frontal regions [11, 20, 23, 24]. A study comprising healthy children [24] showed that both passive listening and active-response story processing yielded activations in the primary auditory cortex and the STG bilaterally and also in the left inferior frontal gyrus (IFG). It has also been shown in TLE patients with atypical language patterns that plastic cortical reorganization can affect frontal and temporal language areas differently with greater reorganization of language circuits in the temporal rather than the frontal lobe [11, 20]. This suggests that productive and receptive functions can be affected by the pathological process in different ways. In contrast with productive tasks, passive tasks are easy to perform, less dependent on patient collaboration and allow the assessment of how fronto-temporal networks contribute to other aspects of language processing. In addition, the pattern of activation of some receptive language paradigms can be as lateralized as that of verbal fluency or semantic decision tasks [11, 20, 22-25]. However, it is also well-known that using a baseline condition such as fixation or rest can lead to more bilateral activations [26]. - The main purpose of this study is to investigate the reliability of a passive, non-collaboration dependent, semantic fmri language task in evaluating language lateralization patterns in a group of selected left and right mesial temporal lobe epilepsy (RMTLE) patients. These results were compared to those of a well-matched healthy group. Based on previous studies, we expected to observe a clear increase of right-hemisphere lateralization associated to earlier age at epilepsy onset in LMTLE patients [12, 27]. Methods (Pages 6-11): - Twenty-three native Spanish patients (15 women) with refractory epilepsy of the temporal lobe were evaluated using an fmri passive language paradigm. Twelve patients had a left hemispheric focus (LMTLE group) with the remaining eleven exhibiting the right (RMTLE group). - We found no statistical differences between groups (n.s, all p > 0.4, see Table 1) in age (RMTLE, LMTLE, controls) or age at epilepsy onset (RMTLE, LMTLE). The study was approved by the Ethical Committee of University Hospital of Bellvitge and informed consent was obtained from all patients and controls. - The stimuli was presented over two runs of a blocked design paradigm. Each run contained three experimental conditions: passive listening to SENs, passive listening to PSENs and rest. SEN and PSEN blocks contained 5 sentences each, with a total block duration of 30 seconds and were each followed by 15 second rest periods. - A general linear model was created using SEN, PSEN and rest conditions and
the motion parameters extracted from the realignment phase. After model estimation, statistical parametrical maps for the SEN and PSEN conditions versus rest and for SEN versus PSEN were created. The first objective of this study was to assess whether a passive semantic task as the one presented could elicit robust activation of the temporal lobe at the subject-level. Thus, individual first level contrasts were inspected in order to compare the activations in individual subjects between active task and rest contrasts (SEN vs. rest, PSEN vs. rest) and contrasts involving only active blocks (SEN vs. PSEN) using a p < 0.001 uncorrected threshold with 20 voxels of cluster extent. The SEN vs. PSEN contrast did not elicit significant differences in around 40% of the subjects (see Results) and no laterality indexes or group contrasts were derived. No further analysis was conducted here as a contrast that shows no robust activations in all participants is of poor clinical use. - Active versus rest contrasts (PSEN vs. rest and SEN vs. rest) however elicited activations at the subject level in 100% of the participants (see Results) and were therefore both well-suited for clinical use. Group activations were then calculated using a one-sample t-test. These contrasts were calculated to provide a general idea of the pattern of activations in each group and therefore are reported at a false discovery rate corrected (FDR-corrected) p < 0.05 threshold with 20 voxels of cluster extent, to correct for multiple comparisons. Results (Pages 11-14): - Task vs. rest contrasts (SEN vs. rest, PSEN vs. rest) thresholded at p < 0.001 uncorrected with 20 voxels of cluster extent and elicited clear activations in the STG and MTG bilaterally in all patients and controls (42 subjects in total, see Figure 1 and Tables 2, 3 and 4 for descriptions of each contrast of interest per group and Figure 4 for single case examples). The contrast between SEN vs. PSEN failed to show significant activations in any cortical region in 4 out of 11 (36%) RMTLE patients, 5 out of 12 (42%) LMTLE patients and in 8 out of 19 (42%) controls and thus was not analyzed any further. - The mean LI and standard deviation for each group and condition can be found in Table 4, while individual LIs are shown for every participant and both SEN vs. rest and PSEN vs. rest contrasts in Figure 2. Discussion (Pages 14-18): - Moreover, an inter-hemispheric dissociation of frontal and temporal language regions in patients with focal epilepsy has also been described [10, 11, 20, 42-44]. In a previous study, 29 (20.1%) out of 144 patients with medically intractable complex-partial seizures showed bilateral language representation after intracarotid amobarbital test assessment [10] and more importantly, 4 (2.8%) of these patients -2 of them with TLE- had strong evidence of an interhemispheric dissociation of expressive and receptive language functions. These findings have been posteriorly confirmed by several functional neuroimaging studies [11, 20, 42-44], which all support the hypothesis that reorganization can affect frontal and temporal language areas differently in patients with atypical language patterns.
- Paradigms used for clinical language mapping vary greatly in different centres and no accepted standardized technique exists. Most fmri language dominance studies in epileptic patients have used active language tasks [13-18]. - Many neuroimaging studies reveal weak neural activity in the right hemisphere in the anatomically equivalent areas to those of the left hemisphere which show a strong singal during language tasks [48,51]. Additionally, some patients with right brain damage have deficits in comprehending natural language [48]. All these data support the idea that although the left hemisphere plays a crucial role in language processing, the right hemisphere also contributes to language comprehension [45, 48, 50, 51, 60]. Hence, the bilateral pattern of temporal lobe activation in controls and MTLE patients using this passive semantic paradigm agrees with previous functional imaging data showing that the STG and MTG are activated bilaterally by both speech and complex non-speech sounds [20, 32, 35, 45, 53-61]. Even when the auditory stimuli is novel and no meaning extraction is possible (as in the PSEN condition) both the MTG and STG show enhanced activations [62, 63]. In fact, some studies have shown that activation at the level of the auditory cortex is neither modulated by the semantic content ( meaningfulness ) of stimuli nor by the type of cognitive task performed [64]. Moreover, in a previous study [35] Words, Pseudowords and Reversed Speech versus baseline bilaterally activated both temporal lobes, yielding less than 2 ml of volumetric difference in activation between hemispheres (the only contrast that showed a significant difference in activation in temporal lobes was Words vs. rest with an LI of 0.11, therefore showing a bilateral distribution). It is also well known that that using a baseline condition such as fixation or rest (as in the SEN vs. rest and PSEN vs. rest contrast) yields bilateral functional patterns and LI values around zero [26]. There is also experimental and clinical evidence showing bilateral activation in conceptual processing [65]. - Moreover, data from lesion and neuroimaging studies suggests that comprehension or semantic activation -involving retrieval and selection of semantic information- depends on a wide cortical network, larger than Wernicke's or even Broca s area (which is required particularly for the correct processing of complex morphosyntactic structures)[67]. Furthermore, there are several patient studies supporting the involvement of the anterior superior temporal lobe for sentence-level comprehension [45, 65, 67, 68]. Semantic knowledge stores are diffusely located in ventral temporal (MTG, ITG, fusiform gyrus, temporal pole) and inferior parietal (angular gyrus) cortices, in addition to the classic posterior STG and planum temporale [23, 45, 48, 50, 69, 70]. Therefore, as both the ventral and anterior temporal lobes are related to receptive language and TLE surgery (ATL) commonly involves the resection of these regions of the temporal lobe, we hypothesize that the passive semantic paradigm presented here -which mainly activates temporal lobe structures- is more precise in predicting semantic language defects, such as naming retrieval or verbal memory decline, in TLE patients who undergo surgery [23, 70-77]. In addition, this paradigm may also provide important information about the extent of functional reserves in the contralateral hemisphere [20] and might be helpful in tailoring the resection of temporal lesions with the aim of preserving eloquent areas of the brain. We
cannot omit however that a limitation of this study is the lack of comparison to other laterality measurements yielded by more classical non-passive language paradigms. Also, a larger sample of patients might have allowed us to compute a more detailed analysis of the LIs within the temporal lobes by dividing the MTL into different sections (i.e, anterior/posterior). Figure 4. - Results are shown over a patient's T1, at a p < 0.05 FDR-corrected threshold with 20 voxels of cluster extent using neurological convention.